This invention relates to a method for the asymmetric synthesis of piperazic acid and derivatives thereof. The method is useful for preparing compounds, especially biologically active compounds, that contain predominantly either a (3R)- or (3S)-piperazic acid moiety. Most particularly, the method may be used to prepare certain caspase inhibitors, such as inhibitors of interleukin-1xcex2 converting enzyme (xe2x80x9cICExe2x80x9d).
Piperazic acid is the common name for hexahydropyridazine-3-carboxylic acid. Since the 3-position bearing the carboxylic acid group is a chiral center, piperazic acid may exist in either the (3S) or (3R) enantiomeric form. The enantiopurity or optical purity of piperazic acid may be conventionally defined in terms of percent enantiomeric excess (%ee) which is the percent of the major enantiomer minus the percent of the minor enantiomer. A racemic mixture has an enantiomeric excess of zero.
The enantiomeric forms of piperazic acid derivatives are important intermediates in natural product synthesis and in the synthesis of biologically useful compounds having non-natural amino acids or peptidomimetic moieties. The angiotensin converting enzyme (xe2x80x9cACExe2x80x9d)inhibitor, Cilazapril(copyright), contains the S-isomer of piperazic acid (Adams et al., Synthetic Comm, 1988, 18, 2225). Recently a class of caspase inhibitors, particularly interleukin-1xcex2 converting enzyme (xe2x80x9cICExe2x80x9d) inhibitors, have been described that also contain piperazic acid, preferably the S-enantiomer (U.S. Pat. Nos. 5,874,424; 5,756,466; 5,716,929; 5,656,627; and 6,204,261). Examples of other pharmacologically active molecules having a piperazic acid moiety include the monamycin family of antibiotics (Bevan et al., J. Chem. Soc. (C), 1971, 522), the azinothricin antitumor antibiotics (see Hale et al., Tetrahedron, 1996, 52, 1047 and references cited therein), verucopeptin (Suguwara et al., J. Antibiotics, 1993, 46, 928), the aurantimycins (Grafe et al., J. Antibiotics, 1995, 48, 119), the C5a antagonist L-156,602 (Hensens et al., J. Antibiotics, 1991, 44, 249), the immunosuppressant IC101 (Ueno et al., J. Antibiotics, 1993, 46, 1658), the oxytocin antagonist L-156,373 (Pettibone et al., Endocrinology, 1989, 125, 217), and the matylastin type-IV collagenase inhibitors (Ogita et al., J. Antibiotics, 1992, 45, 1723; Tamaki et al., Tetrahedron Lett., 1993, 34, 683; Tamaki et al., Tetrahedron Lett., 1993, 34, 8477). Several asymmetric syntheses of piperazic acid and derivatives thereof have been described [Aspinall et al., J. Chem. Soc. Chem. Commun., 1993, 1179; Decicco et al., Syn. Lett., p. 615 (1995); Schmidt et al., Synthesis, p. 223 (1996); Hale et al., Tetrahedron, 1996, 52, 1047; U.S. Pat. No. 5,716,929; and Attwood et al., J. Chem. Soc. Perkin 1, 1986, 1011).
Resolution of enantiomers of piperazic acid from a racemic mixture has been described by Hassell et al., J. Chem. Soc. Perk. Trans. I, pp. 1451 (1979). That method involves using a chiral amine to form a crystalline salt with piperazic acid that has been amino protected. The resulting chiral salt, which is a mixture of diastereomers, is then crystallized from an appropriate solvent to separate the desired isomer from the mixture.
The resulting isomer of piperazic acid may then be esterified by known techniques. Unfortunately, if certain esters are desired, such as the commonly used t-butyl ester, the esterification reaction is slow, low-yielding and may require special laboratory equipment (Hassall et al., supra; PCT publications WO 97/22619 and WO 95/35308).
These syntheses are not desirable on a large scale for one or more of the following reasons: too many steps, less than desirable yields, inconveniently low temperatures, or expensive reagents.
Accordingly, it would be desirable to have an asymmetric synthesis of piperazic acid that is amenable to large-scale synthesis and overcomes the aforementioned shortcomings or otherwise improves upon the current methods. It would also be desirable to have a method of resolving a racemic or enantiomerically enriched piperazic ester in its deprotected form which is stable and may be easily utilized in further reactions.
This invention provides a short, asymmetric synthesis of piperazic acid and derivatives thereof, whereby either the (3S)- or (3R)-enantiomeric form may be obtained with high optical purity. dihydroxyvalerate ester. After the hydroxy groups are converted to suitable leaving groups, such as mesylates, the ester is treated with a bis-protected hydrazine to provide the desired (3S)-piperazic acid derivative. The general scheme is shown below. 
The (3R) enantiomer of piperazic acid may be similarly obtained starting with L-glutamic acid.
The invention also provides a novel method for preparing an enantiomerically enriched piperazic ester from racemic piperazic ester. The method involves the treatment of the piperazic ester with a commercially available enantiomerically enriched acid to produce a crystalline salt. This method is also useful for enhancing the %ee of a piperazic ester prepared by the synthesis of this invention or by other methods known in the art.
By this method, piperazic acid derivatives may be obtained that are useful as intermediates for pharmacologically active compounds. For example, certain intermediates of this invention are useful for preparing caspase inhibitors, particularly inhibitors of ICE, through additional steps known in the art.
Some of the abbreviations used throughout the specifications (including in chemical formulae) are:
Bu=butyl
t-Bu=tert-butyl
Et=ethyl
Cbz=benzoyloxycarbonyl
BOC=tert-butyloxycarbonyl
Alloc=allyloxycarbonyl
Fmoc=fluorenylmethoxycarbonyl
DMF=N,N-dimethylformamide
THF=tetrahydrofuran
MTBE=methyl tert-butyl ether
DCM=dichloromethane
%ee=percent enantiomeric excess.
According to one embodiment, this invention provides a method for preparing a compound having the formula: 
wherein:
R is hydrogen or a carboxyl protecting group;
each R1 and R2 are independently selected from hydrogen or an amino protecting group, wherein R1 and R2 may be taken together to form a fused bicyclic or tricyclic amino protecting group; provided that R1 and R2 are not simultaneously hydrogen;
said process comprising the steps of:
(a) providing a compound of formula II: 
xe2x80x83wherein xe2x80x94OR4 is a suitable leaving group, and
(b) treating II with a compound of formula III: 
in the presence of a suitable organic solvent, a suitable base, and optionally a water scavenger and/or a phase transfer catalyst, to produce I.
As used herein, the following definitions shall apply unless otherwise indicated. It is understood that combinations of substituents or variables are permissible only if such combinations result in stable compounds.
The term xe2x80x9cstable compoundxe2x80x9d, as used herein, refers to a compound sufficiently stable to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40xc2x0 C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
Unless otherwise specified herein, a bond on a chiral carbon atom not depicted with stereochemistry as used herein means that the compound containing the chiral carbon atom may have a %ee between 0 to 100.
The term xe2x80x9ccarboxyl protecting groupxe2x80x9d refers to a moiety that prevents chemical reactions from occuring on the carboxyl group to which that protecting group is attached. A carboxyl protecting group must also be removable by a chemical reaction. Examples of carboxyl protecting groups include esters, such as methyl, ethyl, t-butyl, (un)substituted benzyl, and silyl esters, among others. Other carboxyl protecting groups are well known in the art and are described in detail in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, 1991, published by John Wiley and Sons.
The term xe2x80x9camino protecting groupxe2x80x9d refers to a moiety that prevents chemical reactions from occuring on the nitrogen atom to which that protecting group is attached. An amino protecting group must also be removable by a chemical reaction. Examples of amino protecting groups include carbamates, such as BOC, Cbz, Fmoc, alloc, methyl and ethyl carbamates, among others; cyclic imide derivatives, such as phthalimide; amides, such as formyl, (un)substituted acetyl, and benzoyl; and trialkyl silyl groups, such as t-butyldimethylsilyl and triisopropylsilyl. Other amino protecting groups are well known in the art and are described in detail in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, 1991, published by John Wiley and Sons.
When R1 and R2 taken together with their intervening atoms form a fused ring, a preferred fused ring is a phthalhydrazide.
The term xe2x80x9csuitable organic solventxe2x80x9d refers to a solvent, or a mixture of two or more solvents, which induces conditions which are favorable for the reaction to proceed as intended. Suitable solvents for the alkylation reaction include, but are not limited to, polar, aprotic organic solvents such as DMF, DCM, THF, monoglyme, diglyme, and acetonitrile.
The term xe2x80x9csuitable basexe2x80x9d refers to a reagent, or a mixture of two or more reagents, which facilitates the displacement of a suitable leaving group by a nitrogen of hydrazine III in the alkylation reaction. Suitable bases for the alkylation reaction include, but are not limited to, hydroxides such as sodium hydroxide and lithium hydroxide, alkoxides such as potassium t-butoxide, carbonates of alkaline earth metals such as potassium and sodium carbonate, metal hydrides such as sodium hydride, fluorides such as tetraalkylammonium fluorides (e.g., tetrabutylammonium fluoride (TBAF)), potassium fluoride, cesium fluoride, tertiary organic amines such as 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and alkyl metals exemplified by the alkyl lithiums, such as the butyllithiums.
The present invention is particularly useful in an asymmetric synthesis for making non-racemic (3S)- or (3R)-piperazic acid derivatives. For the asymmetric route, an optically active or non-racemic valerate ester 3 is produced in step (a) from an optically active or non-racemic glutamic acid, as described below. Using this process, piperazic acid derivatives may be obtained having an enantiomeric excess greater than about 90%. 
Non-racemic valerate esters of formula II may be obtained from D- or L-glutamic acid in a few steps following known chemistry. For example, as shown above in Scheme I, (R)-5-oxotetrahydrofuran-2-carboxylic acid (1) is accessible by treating D-glutamic acid with sodium nitrite in dilute sulfuric acid (Schmidt et al., 1996, Synthesis, 223; Qkabe et al., 1988, J. Org. Chem., 53, 4780). Alternatively, the glutamic acid may be treated with potassium nitrite in dilute sulfuric acid or with nitric acid. The carboxylic acid 1 may be esterified by methods known in the art to provide the lactone ester 2, which in turn may be reduced with diisobutyl aluminum hydride (DIBAL) to give the (R)-2,5-dihydroxypentanoate ester 3. By this route, the ester 3 may be obtained with an optical purity of greater than about 90% ee, usually greater than about 95% ee (Ulrich et al., 1996, Synthesis, 226). The R carboxyl protecting group may be an ester, and most preferably t-butyl ester. 
The valerate esters of formula II are obtained by converting the 2,5-dihydroxy groups of ester 3 to suitable leaving groups xe2x80x94OR4, as shown in Scheme II above. A suitable leaving group is a group that will undergo displacement by a nitrogen of hydrazine III, especially in the presence of a base. Examples of suitable xe2x80x94OR4 groups are known in the art (Advanced Organic Chemistry, Jerry March, Fourth Edition) and include alkyl- and arylsulfonates such as mesylate (xe2x80x94OSO2CH3), tosylate (xe2x80x94OSO2-p-C6H4xe2x80x94CH3), triflate (xe2x80x94OSO2CF3), nosylate (xe2x80x94OSO2-p-C6H4xe2x80x94NO2), brosylate (xe2x80x94OSO2-p-C6H4xe2x80x94Br), and silyloxy groups such as t-butyldimethylsilyloxy (xe2x80x94OSi(CH3)2C(CH3)3). Methods for converting hydroxyl groups to such xe2x80x94OR4 groups are well-known. For example, 2,5-dimesylvaleric ester may be obtained from the corresponding diol using methanesulfonyl chloride and triethylamine in dichloromethane according to standard methods (Qabar et al., 1996, Tetrahedron Lett. 37, 965). 
Scheme III above shows step (b) of the asymmetric process: the alkylation reaction of a compound of formula III with a non-racemic compound of formula II to provide the corresponding chiral piperazic acid of formula I. Valerate esters derived from either D- or L-glutamic acid as described above will typically have an enantiopurity of greater than 90% ee, preferably greater than 95% ee. Examples of preferred R1 and R2 groups include Cbz, BOC, alloc, Fmoc and other groups known in the art as amino protecting groups. R1 and R2 taken together may also be a phthalyl group such that hydrazine III is phthalhydrazide: 
The N-alkylation reaction of hydrazine III shown in Scheme III is performed in a suitable organic solvent in the presence of a suitable base. DMF is a preferred solvent. The selection of the base will depend on the strength of the base, the choice of solvent, the temperature of the reaction, the optical purity that is desired and the nature of R1, R2, R4 and R. Generally, the amount of base will be between about 2 to 5 mole equivalents based on the amount of bis-protected hydrazine to be alkylated. Preferred bases for obtaining chiral piperazates include the tetraalkylammonium fluorides such as TBAF.
The temperature at which the alkylation reaction is maintained will depend on the base and solvent, and may be in the range of xe2x88x9235xc2x0 C. to 100xc2x0 C., preferably in the range of about 20xc2x0 C. to 80xc2x0 C. The time of the reaction may vary from about 30 minutes to about 24 hours.
It is preferred that the alkylation reaction be performed under anhydrous or substantially anhydrous conditions. The best results are generally obtained using dry solvents and reagents. Therefore, a water scavenger may be optionally added to the reaction mixture. Any suitable water scavenger, such as sodium sulfate, may be used. The amount of water scavenger to be used will depend on the dryness of the starting solvents and reagents and their propensity to absorb moisture from the air under the reaction conditions and equipment set-up. Another optional reagent that may be added to the alkylation reaction is a phase transfer catalyst such as tetrabutylammonium iodide (TBAI) or tetrabutylammonium bromide (TBAB). When used, the amount of phase transfer catalyst will be in the range of about 0.01 to 1.0 mole equivalents based on the amount of hydrazine III to be alkylated. A preferred phase transfer catalyst is TBAI.
The optical purity of the chiral piperazate I obtained from the alkylation reaction will depend on the reaction conditions and the nature of the R, R1, R2, and R4 groups. For example, when R is t-butyl, R1 and R2 are each Cbz and R4 is mesyl, the use of TBAF in DMF at ambient temperature provides a piperazate I having an optical purity comparable to that of the starting valerate II. Under these conditions, either (R)- or (S)-I may be obtained having an optical purity that is about 90% ee or higher, preferably about 95% ee or higher. The use of potassium carbonate in DMF requires a temperature around 80xc2x0 C. Under such conditions, alkylation of the hydrazine with a valerate ester that is 95% ee or higher will provide about a 70:30 mixture of enantiomers (40% ee). The use of sodium hydride in THF at ambient temperature provides only racemic piperazate. Choosing the necessary combination of base, solvent and temperature will be within the knowledge of one skilled in the art, by reference to the information described herein and the examples given below.
After the alkylation reaction is performed, the piperazic acid derivative I may optionally be separated from the reaction mixture by any standard means known in the art. The details of the conditions used for the methods described above are set forth in the Examples.
As described above, the optical purity of the piperazate I obtained by the synthetic method of this invention may vary according to the reaction conditions used. If desired, the resulting %ee may be further enhanced by a chiral resolution of a compound of formula IV 
said method comprising the step of substantially separating the enantiomeric mixture using suitable physical means;
wherein:
R is a carboxyl protecting group; and
X is a chiral agent.
The term xe2x80x9cchiral agentxe2x80x9d refers to an enantiomerically enriched group which may be ionically or covalently bonded to a nitrogen of a compound of formula IV. Chiral agents which are ionically bonded to said nitrogen include chiral acids. When the chiral agent is a chiral acid, the acid forms a diastereomeric salt with the piperazate nitrogen. The diastereomers are then separated by suitable physical means. Examples of chiral acids include, but are not limited to, tartaric acid, mandelic acid, malic acid, lo-camphorsulfonic acid, and Mosher""s acid, among others. Chiral agents which may be covalently bonded to either of the piperazate nitrogens are known in the art.
The term xe2x80x9cseparated by suitable physical meansxe2x80x9d refers to methods of separating enantiomeric or diastereomeric mixtures. Such methods are well known in the art and include preferential crystallization, distillation, trituration, and crystallization, among others. Chiral agents and separation methods are described in detail in Stereochemistry of Organic Compounds, Eliel, E. L. and Wilen, S. H., 1994, published by John Wiley and Sons.
According to another embodiment, the present invention relates to compounds of formula IV: 
wherein:
R is a carboxyl protecting group; and
X is a chiral agent.
Compound IV may be prepared from I by removing the amino protecting groups R1 and R2. Methods for protecting group removal are well known in the art and described in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, 1991. Compound IV is then formed by treating the resulting amino compound with a chiral agent, as shown in Scheme III below. 
Using the resolution of racemic bis-Cbz, t-butyl piperazate as an example, Scheme IV above depicts the method of forming a compound of formula IV from a compound of formula I, where X is the chiral acid L-tartaric acid. The amino protecting groups were removed by hydrogenation and the resulting amino compound was treated with L-tartaric acid in n-butanol. Under these conditions, the (S)-t-butyl piperazate crystallized out of the solution and was readily isolated by filtration. Other chiral acids are well known to those skilled in the art. The details of the conditions used are set forth in the Examples hereinbelow.
Another embodiment of the present invention comprises the steps of deprotecting the compound of formula I and forming a diastereomeric mixture to provide a compound of formula IV: 
wherein:
R is a carboxyl protecting group;
X is a chiral agent;
said process comprising the steps of:
(a) providing a compound of formula I;
(b) removing R1 and R2 to provide a compound of formula V; and 
(c) treating V with a chiral agent to form IV.
According to another preferred embodiment, the present invention relates to a method of enhancing the %ee of a racemic or enantiomerically enriched compound of formula IV 
wherein:
R is a carboxyl protecting group; and
X is a chiral agent;
comprising the steps of:
(a) preparing a diastereomeric mixture of formula IV 
wherein:
R is a carboxyl protecting group; and
X is a chiral agent;
(b) combining IV with a solvent and heating to reflux to form a solution of IV;
(c) allowing said solution to cool to ambient temperature to cause precipitation of enantiomerically enriched IV; and
(d) filtering the suspension obtained at step (c) and collecting the precipitate, or filtering the suspension obtained at step (c) and collecting the filtrate.
The term xe2x80x9cenantiomerically enrichedxe2x80x9d, as used herein denotes that one enantiomer makes up at least 85% of the preparation. More preferably, the term denotes that at least 90% of the preparation is one of the enantiomers. Most preferably, the term denotes that at least 97.5% of the preparation is one of the enantiomers.
The term xe2x80x9cenhancing the %eexe2x80x9d means that the method provides a piperazic acid derivative with a higher %ee than that of the piperazic acid derivative before using the method.
In a preferred embodiment, X is a chiral acid. In a most preferred embodiment, X is L-tartaric acid or D-tartaric acid. In this method, the use of L-tartaric acid causes precipitation of (S)-piperazic acid or an ester thereof. Conversely, the use of D-tartaric acid causes precipitation of (R)-piperazic acid or an ester thereof. It should be readily apparent to those skilled in the art that enantiomeric enrichment of one enantiomer in the precipitate causes an enantiomeric enrichment in the mother liquor of the other enantiomeric form. Therefore, according to another embodiment, the invention relates to a method of enhancing the %ee of a racemic or enantiomerically enriched compound of formula IV: 
wherein:
R is a carboxyl protecting group; and
X is a chiral agent;
comprising the steps of:
(a) combining a compound of formula IV with a suitable solvent and heating to reflux to form a solution of IV;
(b) allowing said solution to cool to ambient temperature to cause precipitation of enantiomerically enriched IV; and
(c) filtering the suspension obtained at step (b) and collecting the filtrate.
In either method it is preferred that the solvent is a C1-C5 straight or branched alkyl alcohol, most preferably n-butanol. A preferred chiral agent is tartaric acid and R is preferably t-butyl.
Compounds of formula IV where X is L- or D-tartaric acid are highly crystalline solids and readily allow for the separation of piperazate enantiomers. Accordingly, another embodiment relates to a compound of formula B, C, or D: 
wherein R is a carboxyl protecting group; and
X is a chiral agent, preferably L-tartaric acid or D-tartaric acid.
In another preferred embodiment, the precipitate is subjected to an additional crystallization step by adding more alcohol, heating to reflux and allowing the solution to cool to ambient temperature to cause precipitation and further enrichment of one enantiomer. This increases the relative amount of a single enantiomer in the preparation about 90% to greater than 97.5%.
According to another preferred embodiment, the invention relates to a method for preparing an enantiomerically enriched piperazic acid derivative, said method comprising the steps of:
(a) providing a compound of formula II: 
wherein xe2x80x94OR4 is a suitable leaving group;
(b) treating II with a compound of formula III: 
in the presence of a suitable organic solvent and a suitable base to provide a compound of formula I; 
(c) removing R1 and R2 to provide a compound of formula V; 
(d) treating V with a chiral agent to form a compound of formula IV; and 
(e) substantially separating the enantiomeric mixture using suitable physical means to produce a compound of formula IV with an enhanced %ee;
xe2x80x83wherein:
R is hydrogen or a carboxyl protecting group; and
each R1 and R2 are independently selected from hydrogen or an amino protecting group, wherein R1 and R2 may be taken together to form a fused bicyclic or tricyclic amino protecting group; provided that R1 and R2 are not simultaneously hydrogen; and
X is a chiral agent.
According to a preferred embodiment, the method of separating the enantiomeric mixture using suitable physical means comprises the steps:
(a) combining IV with solvent and heating to form a solution of IV; 
(b) allowing said solution to cool to cause precipitation of enantiomerically enriched IV; and
(c) filtering the suspension obtained at step (b) and collecting the precipitate, or filtering the suspension obtained at step (b) and collecting the filtrate;
xe2x80x83wherein:
R is hydrogen or a carboxyl protecting group; and
X is a chiral agent.
The compounds of formula IV or V may be converted in one step by known methods to a useful monoprotected piperazic ester VI. 
A preferred compound of formula VI is the chiral compound of formula VI-a where R is t-butyl and R1 is Cbz. 
The piperazic acid derivative VI may be obtained in chiral form as described above. Chiral VI, especially (S)-VI, is particularly useful as an intermediate for preparing certain pharmacologically active compounds, such as ICE inhibitors or prodrugs thereof exemplified by compound 4 shown below and described in U.S. Pat. Nos. 5,874,424; 5,756,466; 5,716,929; and 5,656,627 (xe2x80x9cVertex Patentsxe2x80x9d) all of which are incorporated by reference. The conversion of piperazic ester VI, especially VI-a, to ICE inhibitors is known (Vertex Patents; Chen et al., 1999, Biorg. Med. Chem. Lett., 9, 1587; Attwood et al., 1986, J. Chem. Soc. Perkin Trans. 1, 1011).
These ICE inhibitors have the general formula VII: 
wherein:
any ring is optionally substituted at any substitutable carbon by Q1, xe2x95x90O, xe2x80x94OH, xe2x80x94COOH, or halogen, and at any nitrogen by R5;
X1 is CH or N;
g is 0 or 1;
m and mxe2x80x2 are independently 0, 1 or 2;
n is 0 or 1;
each J is independently selected from xe2x80x94H, xe2x80x94OH, or xe2x80x94F, provided that when a first and a second J are bound to a C, and said first J is xe2x80x94OH, then said second J is xe2x80x94H;
T is xe2x80x94Ar3, xe2x80x94OH, xe2x80x94CF3, xe2x80x94C(O) xe2x80x94C(O)xe2x80x94OH, xe2x80x94C(O)xe2x80x94OH or any biosteric replacement for xe2x80x94C(O)xe2x80x94OH;
R3 is xe2x80x94CN, xe2x80x94CHxe2x95x90CHxe2x80x94Rg, CHxe2x95x90Nxe2x80x94Oxe2x80x94Rg, xe2x80x94(CH2)1-3xe2x80x94T1xe2x80x94R9, xe2x80x94CJ2xe2x80x94R9, xe2x80x94C(O)xe2x80x94R13, or xe2x80x94C(O)xe2x80x94C(O) xe2x80x94N(R5)(R10);
T1 is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O) xe2x80x94Oxe2x80x94, xe2x80x94C(O) xe2x80x94NR10xe2x80x94, Oxe2x80x94C(O) xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NR10xe2x80x94C(O)xe2x80x94NR10xe2x80x94, xe2x80x94S(O)2xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94S(O)2xe2x80x94or xe2x80x94NR10xe2x80x94S(O)2xe2x80x94NR10xe2x80x94;
each R5 is independently selected from xe2x80x94H, xe2x80x94Ar1, xe2x80x94C(O)xe2x80x94Ar1, xe2x80x94S(O)2xe2x80x94Ar1, xe2x80x94R9, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94S(O)2xe2x80x94NH2, xe2x80x94C(O)xe2x80x94R9, xe2x80x94C(O) xe2x80x94Oxe2x80x94R9, xe2x80x94S(O)2xe2x80x94R9, xe2x80x94C(O) xe2x80x94N(R10) (Ar1), xe2x80x94S(O)2xe2x80x94N (R10) (Ar1), xe2x80x94C(O)xe2x80x94N (R10) (R9), or xe2x80x94S(O)2xe2x80x94N (R10) (R9);
each R9 is a C1-6 straight or branched alkyl group optionally singly or multiply substituted with xe2x80x94OH, xe2x80x94F, xe2x95x90O or Ar1, wherein any R9 may be substituted with a maximum of two Ar1;
each R10 is independently selected from xe2x80x94H or C1-6 straight or branched alkyl;
R13 is xe2x80x94H, xe2x80x94Ar1, xe2x80x94R9, xe2x80x94T1xe2x80x94R9 or xe2x80x94(CH2)1-3xe2x80x94T1xe2x80x94R9;
each Ar1 is a cyclic group independently selected from a monocyclic, bicyclic or tricyclic aryl group containing 6, 10, 12 or 14 carbon atoms; a monocyclic, bicyclic or tricyclic cycloalkyl group containing between 3 and 15 carbon atoms, said cycloalkyl group being optionally benzofused; or a monocyclic, bicyclic or tricyclic heterocycle group containing between 5 and 15 ring atoms and at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94,xe2x95x90Nxe2x80x94, or xe2x80x94NHxe2x80x94, wherein said heterocycle group optionally contains one or more double bonds and optionally comprises one or more aromatic rings;
Ar3 is a cyclic group selected from phenyl, a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring, wherein said heteroaromatic rings comprise from 1-3 heteroatom groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, or xe2x80x94NHxe2x80x94;
wherein each Ar1 or Ar3 is optionally singly or multiply substituted at any ring atom by xe2x80x94NH2, xe2x80x94C(O)xe2x80x94OH, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, 
xe2x80x83or xe2x80x94Q1; and
each Q1 is independently selected from xe2x80x94Ar1, xe2x80x94R9, xe2x80x94T1xe2x80x94R9, or (CH2)1-3xe2x80x94T1xe2x80x94R9; provided that when xe2x80x94Ar1 is substituted with a Q1 which comprises one or more additional xe2x80x94Ar1 groups, said additional xe2x80x94Ar1 groups are not substituted with Q1.
The method of this invention may be used in the synthesis of a compound of formula VII, wherein n is 1 and m is 2.
In another embodiment, the method of this invention may be used in the synthesis of a compound of formula VII, wherein R5 is an acyl moiety selected from xe2x80x94C(O)xe2x80x94Ar1, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94C(O)xe2x80x94R9, xe2x80x94C(O)xe2x80x94Oxe2x80x94R9, xe2x80x94C(O)xe2x80x94N(R10) (Ar1), or xe2x80x94C(O)xe2x80x94N(R10) (R9).
In yet another embodiment, the method of this invention may be used in the synthesis of a compound of formula VII, wherein X1 is CH; each J is H; mxe2x80x2 is 1; T is xe2x80x94COOH or a biosteric replacement for xe2x80x94COOH; g is 0; and R3 is xe2x80x94C(O)xe2x80x94R13.
In a preferred embodiment, the method of this invention may be used in the synthesis of a compound of formula VII-a: 
Alternatively, the method of this invention may be used in the synthesis of a compound of the formula VIII: 
wherein: 
Z is selected from
p is 1 or 2;
each R5, is independently selected from xe2x80x94C(O)xe2x80x94R10, xe2x80x94C(O)Oxe2x80x94R9, xe2x80x94C(O)xe2x80x94N (R10xe2x80x2) (R10xe2x80x2), xe2x80x94S(O)2xe2x80x94R9xe2x80x2, xe2x80x94S(O)2xe2x80x94NHxe2x80x94R10xe2x80x2, xe2x80x94C(O)xe2x80x94CH2xe2x80x94O xe2x80x94R9xe2x80x2, xe2x80x94C(O)C(O)xe2x80x94R10xe2x80x2, xe2x80x94R9xe2x80x2, xe2x80x94H, xe2x80x94C(O)C(O)xe2x80x94OR10xe2x80x2, or xe2x80x94C(O)C(O)xe2x80x94N(R9xe2x80x2) (R10xe2x80x2);
each R9xe2x80x2 is independently selected from xe2x80x94Ar1 or a xe2x80x94C1-6 straight or branched alkyl group optionally substituted with Ar1, wherein the xe2x80x94C1-6 alkyl group is optionally unsaturated;
each R10xe2x80x2 is independently selected from xe2x80x94H, xe2x80x94Ar1, a xe2x80x94C3-6 cycloalkyl group, or a xe2x80x94C1-6 straight or branched alkyl group optionally substituted with Ar3xe2x80x2, wherein the xe2x80x94C1-6 alkyl group is optionally unsaturated;
R13xe2x80x2 is selected from H, Ar1, or a C1-6 straight or branched alkyl group optionally substituted with Ar1, xe2x80x94CONH2, xe2x80x94OR5xe2x80x2, xe2x80x94OH, xe2x80x94OR9xe2x80x2, or xe2x80x94CO2H;
each R51 is independently selected from R9xe2x80x2, xe2x80x94C(O)xe2x80x94R9xe2x80x2, xe2x80x94C (O)xe2x80x94N(H)xe2x80x94R9xe2x80x2, or two R51 taken together form a saturated 4-8 member carbocyclic ring or heterocyclic ring containing xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94;
each R21 is independently selected from xe2x80x94H or a xe2x80x94C1-6 straight or branched alkyl group;
Y2 is xe2x80x94H2 or xe2x95x90O
each Ar1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, SO2, xe2x95x90Nxe2x80x94, and xe2x80x94NHxe2x80x94, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by xe2x80x94Q1;
each Q1 is independently selected from the group consisting of xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, R5xe2x80x2, xe2x80x94OR5xe2x80x2, xe2x80x94NHR5xe2x80x2, OR9xe2x80x2, 
xe2x80x94N(R9xe2x80x2)(R10xe2x80x2), R9xe2x80x2, xe2x80x94C(O)xe2x80x94R10xe2x80x2, and
provided that when xe2x80x94Ar1 is substituted with a Q1 group which comprises one or more additional xe2x80x94Ar1 groups, said additional xe2x80x94Ar1 groups are not substituted with another xe2x80x94Ar1.
Preferably, the method of this invention is used in the synthesis of a compound of formula VIII, wherein Y2 is O and R21 is H.
In another preferred embodiment, the method of this invention is used in the synthesis of a compound of formula VIII, wherein R5xe2x80x2 is selected from xe2x80x94C(O)xe2x80x94R10xe2x80x2, xe2x80x94C(O)Oxe2x80x94R9xe2x80x2, xe2x80x94C(O)xe2x80x94N(R10xe2x80x2) (R10xe2x80x2) xe2x80x94C(O)xe2x80x94CH2xe2x80x94O xe2x80x94R9xe2x80x2, xe2x80x94C(O)C(O)xe2x80x94R10xe2x80x2, xe2x80x94C(O)C(O)xe2x80x94OR10xe2x80x2, or xe2x80x94C(O)C(O)xe2x80x94N (R9xe2x80x2) (R10xe2x80x2).
In yet another preferred embodiment, the method of this invention is used in the synthesis of a compound of formula VIII, wherein Z is 
p is 1 and R51 is selected from xe2x80x94Ar1, xe2x80x94C1-6 straight or branched alkyl or xe2x80x94C1-6 straight or branched alkyl substituted with Ar1.
A particularly preferred embodiment relates to using the method of this invention in the synthesis of ICE inhibitors 4 shown below. 
4-a, R=Et or 4-b, R=CH2Ph
A key intermediate in the synthesis of the aforementioned ICE inhibitors is (1S, 9S)-9-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid (IX-a) having the xe2x80x9c7,6xe2x80x9d ring system. (S)-VI-a described above may be converted to IX-a and other useful intermediates having 7,6 ring system such as X and XI following known chemistry as shown in Scheme V. 
Reagents and conditions: (a) PCl5, CH2Cl2; (b) NaHCO3 (aq); (c) H2, Pd/c, MeOH; (d) SOCl2, N-methylmorpholine, THF; (e) hydrazine hydrate, EtOH; (f) 50% trifluoroacetic acid, CH2Cl2.
Scheme V above depicts the conversion of (S) -VI to compounds having the 7,6 ring system, specifically compounds IX, X, and XI. N-Phthaloylglutamic acid xcex3-benzyl ester (5) was converted to the acid chloride 6 with PCl5 in CH2Cl2 under conditions well known in the art. Acid chloride 6 was coupled to (S)-VI-a in aqueous sodium bicarbonate to form the bis-Cbz intermediate 7. The two Cbz groups of compound 7 were simultaneously removed by hydrogenation in the presence of Pd/C in methanol to form 8. Cyclization of 8 to form the 7,6 compound X was achieved by treating 8 with thionyl chloride and N-methylmorpholine in THF.
Compound X may be transformed to other useful intermediates having the 7,6 ring system by deprotecting either one or both of the protecting groups. By removing the phthalimide protecting group, compounds of formula IX are obtained. By removing the ester, compounds of formula XI are obtained. The details of the conditions used for the above described synthetic steps are set forth in the Examples hereinbelow.
Using the preparation of compound 4 as an example, Scheme VI below depicts the synthesis of compounds of formula VIII from compound IX-b. 
Compound 4-b may be prepared from IX-b by the methods described in U.S. Pat. No. 6,204,261, the disclosure of which is herein incorporated by reference.